Answers to the questions posed in this proposal would offer insights to one of the most difficult and intriguing of developmental processes, the formation of neural connections in the embryonic central nervous system of vertebrates. Two specific issues are addressed: (1) How are nerve fibers guided to their proper targets in the developing central nervous system? (2) What factors influence the formation of functional connections between these processes and their target cells? The majority of the experiments described use embryonic surgery on amphibians, different genotypes, or different embryonic stages will be used to explicitly test proposed roles for (1) diffusable factors, (2) neural impulse activity, (3) timing. Results from these experiments will be further pursued by asking (1) whether cues that are used in the formation of neural pathways are common to different vertebrate species, (2) if the elimination of any single cue does not interfere with axonal navigation whether the elimination of combinations of cues does so, and (3) whether we can demonstrate axonal navigation to a target in vitro. A culture system with time-lapse video recording will also be used to assay turning responses to retinal axons to factors exuded by or extracted from target tissues. The long term goal of this research would be to identify specific biological factors and their roles in neural development. Such knowledge would allow us to focus attention on these factors individually and finally come to a cellular and molecular understanding of the formation of neural connections. Such knowledge might also be of significant medical value with respect to the prevention and treatment of malformation in human fetal brain.